Simulating an Infection Growth Model in Certain Healthy Metabolic Pathways of <i>Homo sapiens</i> for Highlighting Their Role in Type I <i>Diabetes mellitus</i> Using Fire-Spread Strategy, Feedbacks and Sensitivities

<div><p>Disease Systems Biology is an area of life sciences, which is not very well understood to date. Analyzing infections and their spread in healthy metabolite networks can be one of the focussed areas in this regard. We have proposed a theory based on the classical forest fire model for analyzing the path of infection spread in healthy metabolic pathways. The theory suggests that when fire erupts in a forest, it spreads, and the surrounding trees also catch fire. Similarly, when we consider a metabolic network, the infection caused in the metabolites of the network spreads like a fire. We have constructed a simulation model which is used to study the infection caused in the metabolic networks from the start of infection, to spread and ultimately combating it. For implementation, we have used two approaches, first, based on quantitative strategies using ordinary differential equations and second, using graph-theory based properties. Furthermore, we are using certain probabilistic scores to complete this task and for interpreting the harm caused in the network, given by a ‘critical value’ to check whether the infection can be cured or not. We have tested our simulation model on metabolic pathways involved in Type I <i>Diabetes mellitus</i> in <i>Homo sapiens</i>. For validating our results biologically, we have used sensitivity analysis, both local and global, as well as for identifying the role of feedbacks in spreading infection in metabolic pathways. Moreover, information in literature has also been used to validate the results. The metabolic network datasets have been collected from the Kyoto Encyclopedia of Genes and Genomes (KEGG).</p></div

Displaying the concept behind the construction of integrated pathway system that includes SAg expression regulatory pathway of <i>S. aureus</i> and TCR signaling pathway of an infected host (<i>H. sapiens</i>).

<p>Displaying the concept behind the construction of integrated pathway system that includes SAg expression regulatory pathway of <i>S. aureus</i> and TCR signaling pathway of an infected host (<i>H. sapiens</i>).</p

Diagram showing the studied biochemical pathways upon perturbed/unperturbed conditions, along with different conflicting objective functions.

<p>Diagram showing the studied biochemical pathways upon perturbed/unperturbed conditions, along with different conflicting objective functions.</p

Structural disorder: a tool for housekeeping proteins performing tissue-specific interactions

<p>An interaction between a pair of proteins unique for a particular tissue is denoted as a tissue-specific interaction (TSI). Tissue-specific (TS) proteins always perform TSIs with a limited number of interacting partners. However, it has been claimed that housekeeping (HK) proteins frequently take part in TSIs. This is actually an unusual phenomenon. How a single HK protein mediates TSIs – remains an interesting yet an unsolved question. We have hypothesized that HK proteins have attained a high degree of structural flexibility to modulate TSIs efficiently. We have observed that HK proteins are selected to be intrinsically disordered compared to TS proteins. Therefore, the purposeful adaptation of structural disorder brings out special advantages for HK proteins compared to TS proteins. We have demonstrated that TSIs may play vital roles in shaping the molecular adaptation of disordered regions within HK proteins. We also have noticed that HK proteins, mediating a huge number of TSIs, have a greater portion of their interacting interfaces overlapped with the adjacent disordered segment. Moreover, these HK proteins, mediating TSIs, preferably adapt single domain (SD). We have concluded that HK proteins adapt a high degree of structural flexibility to mediate TSIs. Besides, having a SD along with structural flexibility is more economic than maintaining multiple domains with a rigid structure. This assists them in attaining various structural conformations upon binding to their partners, thereby designing an economically optimum molecular system.</p

Analyzing the spread of infection and combat process in a hypothetical metabolic network; nodes represent metabolites, edges represent reaction links, bold lines signify infection, dotted lines signify combat.

<p>Analyzing the spread of infection and combat process in a hypothetical metabolic network; nodes represent metabolites, edges represent reaction links, bold lines signify infection, dotted lines signify combat.</p

Effects on some of the TCR signaling molecules upon perturbing the concentrations of ZAP70, LCK and FYN for unperturbed and perturbed TCR signaling pathways of <i>H. sapiens</i>.

<p>Effects on some of the TCR signaling molecules upon perturbing the concentrations of ZAP70, LCK and FYN for unperturbed and perturbed TCR signaling pathways of <i>H. sapiens</i>.</p

Comparison of some of the computed <i>c</i>-values for given signaling molecules with the existing experimental evidences, for biological validation purpose.

<p>Here, ‘un’ denotes unperturbed TCR signaling pathway and ‘per’ refers to perturbed conditions with conflicting objective function optimization.</p

TCR signaling pathway of <i>H. sapiens</i>.

<p>SEB refers to Staphylococcal Enterotoxin B. Sharp arrow head indicates activation and blocked arrow shows inhibition.</p

Schematic representation of certain feedback reactions that are predominant in metabolic pathways in <i>H. sapiens</i>; A–D, X and Y denote metabolites, and a–d and d' signify reaction links/genes.

<p>Schematic representation of certain feedback reactions that are predominant in metabolic pathways in <i>H. sapiens</i>; A–D, X and Y denote metabolites, and a–d and d' signify reaction links/genes.</p

A schematic model of SAg of <i>S. aureus</i> interaction with TCR and MHC class II molecules of an infected <i>H. sapiens</i>.

<p>Here, one can find the difference between antigen and SAg binding site on TCR.</p